Science of Medicines Week 10 Flashcards
define bioavailability
a measure of the amount of drug that reaches its site of action AND the rate at which it gets there
define pharmacokinetics
what the body does to the drug
define pharmacodynamics
what the drug does to the body
define extravascular administration
not injecting into the blood e.g. tablet
What two steps does a drug need to achieve after administration to get into the systemic circulation?
- release
- absorption
define release
the drug dissolving at the administration site
define absorption
the drug crossing the biomembrane to reach the blood
What are the 2 steps of dissolution of a solid crystal in a liquid?
- solvation of the drug at the crystal surface to create a stagnant layer of saturated solution –> called the diffusion layer
- diffusion of the dissolved molecules across the diffusion layer into the bulk solution
Which equations gives the overall rate of dissolution at constant temperature?
Noyes-Whitney equation
Which 3 factors can be used to predict the solubility of a weakly acidic or basic drugs?
pH of solution, pKa, solubility of the unionised form (S0)
What are the 3 methods of membrane transport in the transcellular pathway?
- passive diffusion
- aqueous pore
- facilitated diffusion
- active transport
What is the equation used to calculate flux (diffusion)?
J= C x v x A
What does Fick’s 1st law describe?
rate of passive transport
What are the membrane properties affecting passive transport?
membrane thickness (h) and membrane area (A)
What are the drug properties affecting passive transport?
concentration gradient (C1-C2) and partition coefficient (K)
What are the drug and membrane properties affecting passive transport?
diffusivity (D)
What is used to give a drug’s lipophilicity?
LogP
drug that is 10x more lipid soluble than water soluble…
P=10
LogP=1
drug that is 100x more lipid soluble than water soluble…
P=100
LogP= 2
drug that is 5x more water soluble than lipid soluble…
P= 0.2
LogP= -0.7
What does Lipinski’s rule of 5 predict?
whether a drug will have good oral bioavailability
What are Lipinski’s 5 rules?
- molecular weight is less than 500
- LogP is less than/equal to 5
- no more than 5 hydrogen bond donors
- no more than 10 hydrogen bond acceptors
- all units are multiples of 5
define therapeutic window
the area of concentration of drug on a graph to have the efficacy needed
Why is insulin administered by subcutaneous injection?
pepsin degrades polypeptides in the stomach, do cannot be administered orally
What is the order of the rate of the stomach gradually releasing its contents into the small intestine?
zero order
What is the order of the rate of the stomach gradually releasing its contents into the small intestine if in a fasted state?
first order
What are 8 factors that affect gastric emptying and therefore drug absorption?
- meal volume
- type of meal
- physical state of stomach contents
- chemicals
- drugs
- body position
- disease
- exercise
How does meal volume affect gastric emptying?
the larger the meal, the quicker the INITIAL gastric emptying
How does the type of meal affect gastric emptying?
fatty acids, triglycerides, carbohydrates and amino acids all reduce gastric emptying rate
How does physical state of stomach contents affect gastric emptying?
solutions or suspensions of small particles empty quicker than chunks of material
How do chemicals affect gastric emptying?
- acids reduce emptying rate
- alkalis increase emptying rate at low concentrations and decrease it at higher concentrations
How do drugs affect gastric emptying?
drugs including anticholinergics, narcotics, ethanol all reduce emptying rate
How does body position affect gastric emptying?
lying on the left side reduces emptying rate
How does disease affect gastric emptying?
emptying rate is reduced by the presence of ulcers and in some diabetics
How does exercise affect gastric emptying?
vigorous exercise reduces emptying rate
How does gastric emptying time affect drug absorption?
the longer the gastric emptying time, the longer it will take for the drug to appear in the systemic circulation
What is one way membrane permeability can be increased?
using prodrugs
How can using prodrugs increase membrane permeability?
can use a prodrug with high permeability, and after crossing the membrane, there are enzymes which convert the drug into its active form
How may the stomach degrade drugs?
HCl= degrades some, so gastro-resistant coatings are needed
Pepsin= digestive protease destroys polypeptide drugs
How may drugs be degraded in the duodenum?
Trypin, chymotrypsin, elastase, carboxypeptidase A and B degrade many large proteins
How may drugs be degraded in the small intestine?
Cytochrome P450 enzymes
Esterases
Glucuronosyl transferases transfer glucuronic acid to nucleophilic sites on drugs
How may drugs be degraded in the colon?
gut flora can metabolise and inactive drugs
What is the hepatic first pass effect?
- drug passes intestinal membrane into systemic circulation
- drug is transport to liver via hepatic portal vein
- some drug is metabolised
- reduces bioavailability of the drug
What are the 4 processes of transportation of drugs across the GI membrane?
paracellular transport, diffusion, facilitated diffusion, drug transporters
define efflux pump
a cellular protein that can prevent intracellular accumulation of drug by pumping the drug that enters the cell immediately back out
How can P-glycoprotein inhibitors help with cancer treatment?
- P-glycoprotein is an efflux pump that prevents chemotherapeutic drugs entering cancerous cells
- also prevents oral delivery due to presence in intestinal epithelial cells
- co-administration prevents drug efflux
What are the 4 types of absorption rates for oral dosage forms?
- rapid release
- delayed release
- slow release (zero order kinetics)
- slow release (1st order kinetics)
What is Cmax and Tmax?
Cmax = maximum concentration in serum
Tmax = time taken to reach maximum concentration (Cmax)
What are the characteristics of delayed absorption on a graph?
delayed and fast absorption have the same Cmax values but different Tmax due to a large lag time
What does the amount of a first order absorption drug absorbed per unit depend on?
concentration of drug at the site of absorption -> the greater the amount to be absorbed the faster the absorption rate
Is drug absorption for zero order absorption dependent on quantity of drug at site of absorption?
no, the amount released per unit time is constant, for example by a particular tablet coating method
How must tetracyclines be taken?
on fasted stomach as GI absorption is decreased by Al, Ca, Mg and Fe presence (also milk products!)
What can’t you take antacids with?
milk products as the calcium can react with them and prevent them being absorbed
